[unreadable] [unreadable] This proposal is in response to RFA-NS-02-012 entitled "NEURODEGENERATIVE DISEASE ASSAYS FOR HIGH THROUGHPUT DRUG SCREENING AND CHEMICAL GENETICS." The aims are directed toward the problem of neurofibrillary pathology, which occurs in at least twenty different disease settings, but most commonly in Alzheimer's disease. The key protein involved in these diseases is the tau protein, which is altered in its microtubule binding properties, and once dissociated from the microtubules self-assembles into intra-cellular inclusions called neurofibrillary tangles. Whether neurofibrillary pathology represents a suitable target has been hotly debated. However, the findings of tan mutations that cause fronto-temporal dementia and the development of mouse models with neurofibrillary lesions all lead to the inescapable conclusion that tau can only be validated as a target by compounds that alter neurofibrillary pathology. We propose to develop two assays--a targeted in vitro assay and a cell-based assay--for configuration into a high throughput format to identify compounds with potential effects on neurofibrillary lesions. The in vitro assay targets the cdk5/p25 complex, which is known to phosphorylate tau under pathological conditions and disrupt tau binding to microtubules. The cell-based assay will identify compounds that enhance the binding of tau to microtubules, a process under complex control mechanisms that include the phosphorylation state of tan. This proposal principally involves work at two sites. They are the Kosik laboratory in the Center for Neurologic Diseases and the Laboratory for Drug Discovery for Neurodegeneration (LDDN) under the direction of Ross Stein. [unreadable] [unreadable]